1. Field of the Invention
The present invention relates to the treatment of lung conditions, and in particular, the treatment of lung conditions involving reduced or suppressed levels of endogenous surfactant production, through the use of gamma interferon-containing compositions.
2. Description of the Related Art
Millions of individuals worldwide are afflicted annually with debilitating lung diseases. The lives of many of these individuals will be lost, and the lives of the rest made much less comfortable, by diseases of the lung. Respiratory distress syndromes (RDS), which comprise a significant proportion and variety of lung diseases, are particularly troublesome due to the high mortality rates associated with the various types of RDS disease. For example, in adult respiratory distress syndrome (ARDS), a mortality rate of greater than 50% is observed. Moreover, in premature infants a similar mortality rate is seen in Hyaline membrane disease, at least in smaller premature infants.
Normal lung function depends on the presence of an alveolar lining layer with properties that permit alternate increases and decreases in surface tension, thus allowing continuous sorption and desorption of respiratory gases. To function properly in the exchange of gases, and to maintain its structural integrity, the alveolar lining must retain its elasticity. The principal mechanism employed by the body to maintain alveolar elasticity is through the production of surfactant, primarily by type II alveolar cells. When these cells fail to produce a sufficient amount of surfactant, or one or more of its components, the alveolar elasticity is decreased or lost, resulting in reduced gas exchange and often alveolar collapse.
Respiratory distress syndrome is a descriptive term that has been applied to many acute, diffuse infiltrative lung lesions of diverse etiologies when they are accompanied by arterial hypoxemia. Diseases classified generally as respiratory distress syndromes range from adult respiratory distress syndromes (ARDS) to a neonatal form, termed variously as idiopathic RDS or hyaline membrane disease. The term RDS is applied to the various forms because of several clinical and pathologic similarities between such acute illnesses in adult and neonatal forms. However, in the neonatal form, immaturity of alveolar surfactant production and a highly compliant chest wall are primarily involved in the pathophysiology, whereas in the adult forms, alveolar surfactant changes are secondary to the primary process, and the chest wall is not compliant.
Adult respiratory distress syndrome includes diseases of numerous etiologies, ranging from diffuse pulmonary infection (e.g., viral, bacterial, fungal, pneumocystis, etc.), inhalation of toxins and irritants, narcotic overdose and other drug effects, immunologic responses, endotoxin shock, nonthoracic trauma with hypotension, and even postcardiopulmonary bypass (e.g., "pump lung" or "post-perfusion lung"). Regardless of the etiology, ARDS is invariably associated with increased liquid in the lungs. Moreover, certain of these conditions have as a secondary process an underlying reduction in surfactant content of one or more surfactant components. It is these conditions involving a reduction in lung surfactant with which the present invention is concerned.
While decreased surfactant content plays a role in RDS and ARDS of various etiologies, this problem is symptomatic of RDS in premature infants. In this disease, often referred to as hyaline membrane disease or idiopathic RDS, surfactant deficiency is generally due to its "immaturity" with respect to the synthesis of one or more surfactant components. While the disease affects greater than 60% of very premature children, idiopathic RDS is not limited exclusively to premature infants and various forms may afflict term children.
In contrast to ARDS, idiopathic RDS has a more restricted etiology, occurring primarily in infants who are premature, but also in infants having a familial disposition to RDS, those with acidosis, C-section infants, and infants suffering from intrapartum asphyxia. There has been no indication, however, that idiopathic RDS is caused by exogenous trauma or infections of the lungs per se, viral or otherwise. In all cases of idiopathic RDS, immaturity of alveolar surfactant production or overall non-production appears to be a primary cause. In such infants, alveolar atelectasis, hyaline membrane formation and interstitial edema make the lungs less compliant, requiring greater pressure to expand the small alveoli and airways. Deficient synthesis or release of surfactant, together with small respiratory units and compliant chest wall, results in atelectasis, rapid respiratory rate, etc. Pulmonary blood flow is thus reduced with ischemic injury to lecithin producing cells and the vascular bed, resulting in an effusion of proteinaceous material into the alveolar spaces.
Natural lung surfactant is a lipid composition which includes a complex mixture of primarily phospholipids and proteins, with lipids making up about 99% of the composition. The lipid component is composed mainly of dipalmitoyl phosphatidylcholine (dipalmitoyl lecithin), phosphatidyl glycerol, phosphatidyl ethanolamine and other lipids and phospholipids. The protein components of surfactant, required for full surfactant properties, include primarily two apoprotein species. The larger of these two proteins is a species demonstrating size heterogeneity of between about 29,000 and 36,000 daltons. (see, e.g., King et al. (1972), Am. Jrnl. Physiol., 223:715-726; PCT publication number WO 86/03408). A second protein species, also thought to be a mixture, has been identified in surfactant as having a molecular weight in the range of about 6 to 14 kilodaltons. In both cases, the size heterogeneity exhibited by these proteins is believed to represent, at least in part, varying degrees of glycosylation of peptide species. Importantly, the presence of these two apoproteins has been shown to enhance the rate of surface-film formation. (see, e.g., Whitsett et al. (1986), Pediatr. Res., 20:460; Avery et al. (1986), New Engl. Jrnl. Med., 315:825).
The treatment of respiratory distress diseases, including both adult and idiopathic RDS, has traditionally been limited to supportive care including, for example, oxygen administration or even mechanical ventilation. Forced ventilation is not only an inadequate treatment in most severe cases of RDS and surfactant-deficiency RDS, it places mechanical stress on the lungs and diaphragm and can lead to severe alveolar trauma or even pneumothorax.
More recently, some success in the treatment of RDS, particularly idiopathic RDS, has been reported with both natural and synthetic surfactants (see, e.g., Kwong et al. (1985), Pediatrics, 76:585; Mervitt et al. (1986), New Engl. Jrnl. Med., 315:785; Whitsett et al., supra). In these instances, various surfactant mixtures are typically applied directly to lung tissues by installation in an attempt to replenish lung surfactant contact exogenously. Corticosteroids have also found some utility in the treatment of RDS, particularly when administered to expectant mothers of premature infants (see, e.g., Ballard et al. (1980), J. Pediatr., 97:451; Papageorgiou et al. (1981), Pediatrics, 67:416).
Unfortunately, present treatment protocols such as the foregoing are far from ideal or even adequate in the treatment of all cases of RDS. While shown to be effective in certain instances, both natural and synthetic surfactants are expensive, often difficult to prepare, and not always successful. Moreover, other than natural extracts of human tissues or those employing human recombinant proteins, most preparations are devoid of human surfactant proteins. Corticosteroid therapy is also undesirable under certain circumstances, for example, as a direct treatment in premature infants or in patients sensitive to corticosteroids. In any case, there is currently a great need for additional approaches to the treatment of lung diseases, and particularly, to the treatment of diseases or conditions wherein there is a need to increase lung surfactant content.